The proposed study is a 12-year follow-up of a large cohort (N=446) of offspring at risk for panic disorder (PD), and comparison offspring at risk for major depression (MD) or without vulnerability for mood or anxiety disorders. The children were originally recruited in toddler hood and early childhood, were reassessed in middle childhood (at Year 6), and will enter adolescence during the next wave. This sample is unique in that a) children were characterized extensively at Baseline, using laboratory measures of behavioral inhibition (BI) and assessments of nascent symptomatology well before they entered the period of risk for childhood anxiety disorders; b) proband parents underwent comprehensive assessments of their adult and childhood psychopathology, with careful attention to delineating episodes to which offspring might have been exposed; and c) to our knowledge, it represents the largest sample of children at risk for anxiety followed longitudinally to date. Our study is also unique in that it has spawned offshoots in several promising directions, including studies of the genetic bases of BI and of an early intervention for young children at risk for anxiety. Our ongoing goals have been to study whether it is possible to predict the development and sequence of anxiety disorders among children of parents with PD, as well as to identify risk factors for childhood psychopathology, including temperamental (behavioral inhibition or disinhibition [BD]), parental comorbidity, and psychosocial adversity factors which might influence or moderate risk. We have already identified increased risks in middle childhood for PD, agoraphobia, and multiple anxiety disorders in offspring of PD parents, for a range of anxiety, mood and disruptive behavior disorders in offspring of MD parents, for social anxiety in BI youngsters, and for disruptive behavior disorders in children with BD. We have also noted associations between risk for anxiety disorders and perinatal and psychosocial risk factors. Now, as the children enter adolescence, a period of heightened risk for onset of social phobia, PD, and MD, as well as alcohol and substance abuse, peer difficulties, and other psychosocial problems, we are in the exciting and unique position to answer questions about the specific vulnerabilities conferred by parental PD, parental MD, BI or BD, and pre-existing childhood disorders. We are also able to begin to ask why and how the risk factors we have identified early in childhood influence psychopathology or resiliency in adolescence, and in what ways they combine with protective factors in predicting outcome. These research questions are straightforward, yet they carry broad implications. Studies of high-risk children and adolescents are of the utmost major public health relevance, since the identification of predictors of psychopathology and substance use disorders can set the stage for targeted primary or secondary prevention programs. The identification of such predictors, whether constitutional or environmental, is essential if we are to understand why some children with biological or psychosocial risk factors remain healthy during adolescence and successfully negotiate developmental tasks of this period while others develop psychopathology or derailments in functioning. Careful articulation of the mechanisms by which such factors operate would enable the design of specific, efficient, and cost-effective interventions to prevent poor outcomes in adolescence, and would permit the targeting of scarce societal resources for populations most likely to benefit from such programs.